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Mechanism of Action

Acyclovir is an antiviral drug [see Microbiology].


Absorption and Distribution


Single dose application of SITAVIG containing 50 mg of acyclovir to the buccal mucosa in 12 healthy volunteers provided mean maximum salivary concentrations of 440 μg/mL 8 hours after application of the tablet. The pharmacokinetic parameters of acyclovir in the saliva of healthy volunteers are provided in Table 2.

Table 2: Pharmacokinetic (PK) Parameters of Acyclovir in Saliva Following Application of a Single SITAVIG 50 mg Tablet in Healthy Volunteers (N = 12)

Salivary PK Parameters
(N = 12)
Mean ±SD
(Min - Max)
AUC0-24h (mcg.h/mL) 2900 ± 2400 (849 - 9450)
Cmax (mcg/mL) 440±241 (149 - 959)
Tmax (hour) 7.95 ± 4.08 (3.07 - 18.05)

In the Phase 3 study, the levels of acyclovir in saliva were measured within 24 hours of SITAVIG application in 56 patients with recurrent herpes labialis (mean value 88.1 micrograms per mL) and were within the range of those observed in the PK study in healthy volunteers.

In healthy volunteers, the median duration of buccal adhesion was 14 hours following application of a single SITAVIG 50 mg tablet.


Plasma concentrations of acyclovir were measured in 12 healthy volunteers after a single-dose application of SITAVIG 50 mg buccal tablet. Acyclovir concentrations had a delayed appearance (undetectable at 5 hours) and were below the concentrations required for antiviral activity (range: 17.5 to 55.3 nanogram per mL).

Metabolism and Excretion

Acyclovir is metabolized to 9-[(carboxymethoxy)methyl]guanine (CMMG) and 8hydroxy-acyclovir (8-OH-ACV) by oxidation and hydroxylation, and is primarily excreted unchanged by the kidneys.

Food Effect

There was no formal food effect study conducted with SITAVIG; however, in clinical studies patients were allowed to eat and drink while taking SITAVIG.


Mechanism of Action

Acyclovir is a synthetic purine nucleoside that is phosphorylated intracellularly by the viral encoded thymidine kinase (TK) of HSV into acyclovir monophosphate, a nucleotide analogue. The monophosphate is further converted into diphosphate by cellular guanylate kinase and into triphosphate by a number of cellular enzymes. In a biochemical reaction, acyclovir triphosphate inhibits replication of herpes viral DNA by competing with nucleotides for binding to the viral DNA polymerase and by incorporation into and termination of the growing viral DNA chain. The cellular thymidine kinase of normal, uninfected cells does not use acyclovir effectively as a substrate, hence toxicity to mammalian host cells is low.

Antiviral activity

The quantitative relationship between the cell culture susceptibility of herpes viruses to antivirals and the clinical response to therapy has not been established in humans, and virus sensitivity testing has not been standardized. Sensitivity testing results, expressed as the concentration of drug required to inhibit by 50% the growth of virus in cell culture (EC50), vary greatly depending upon a number of factors. Using plaque-reduction assays on Vero cells, the median EC50 value of acyclovir against clinical herpes virus isolates (subjects receiving placebo) was 1.3 μM (range: < 0.56 to 3.3 μM).

Drug Resistance

Resistance of HSV to acyclovir can result from qualitative and quantitative changes in the viral TK and/or DNA polymerase. Clinical isolates of HSV with reduced susceptibility to acyclovir have been recovered from immunocompromised subjects, especially with advanced HIV infection. While most of the acyclovir-resistant mutant isolates from immunocompromised subjects thus far have been found to be TK-deficient, other mutant isolates involving the viral TK gene (TK partial and TK altered) or DNA polymerase have been identified. TK-negative mutants may cause severe disease in infants and immunocompromised adults.

The possibility of viral resistance to acyclovir should be considered in immunocompromised subjects who show poor clinical response during therapy.

Clinical Studies

Study in Patients with Recurrent Herpes Labialis (cold sores)

The efficacy and safety of SITAVIG was evaluated in a randomized, double-blind, placebo-controlled, patient-initiated, multicenter trial comparing SITAVIG 50 mg administered as a single dose (n = 378) to placebo (n = 397) in patients with recurrent herpes labialis (cold sores). A total of 376 SITAVIG treated patients and 395 placebo treated patients were included in the Intent to Treat (ITT) efficacy population defined as all patients who took study treatment and who had a start date and time of treatment initiation recorded. The mean age was 41.0 years (range: 18-80 years) and the majority of patients were female (68.6%), and Caucasian (94.9%). All patients had at least 4 herpes episodes in the previous year of whom 68.4% had ≥ 5 episodes. Patients were instructed to initiate treatment within one hour after the onset of prodromal symptoms and before the appearance of any signs of herpes labialis lesions by applying the tablet to the buccal mucosa in the canine fossa. If the tablet was detached within the first 6 hours, subjects were instructed to reapply a tablet.

The mean and median durations of the recurrent herpes labialis episode (ITT population, n=771) were approximately half a day shorter in patients treated with SITAVIG compared with patients treated with placebo.

Last reviewed on RxList: 10/31/2016
This monograph has been modified to include the generic and brand name in many instances.

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